Clinical Neurochemistry

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Clinical Neurochemistry The Soup
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A good working knowledge of clinical
neurochemistry is essential for understanding and
treating neurological and psychiatric disorders.
It is important to learn the basics now so you
can update your clinical management as new
information becomes available.
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What You Should Know

• Primary cell bodies, sites of action and
  metabolic pathways for dopamine, norepinepherine,
  serotonin, acetylcholine, GABA and glutamate
• Know the main mechanism of action and termination
  of action of the most common neurotransmitters
• Be aware of the most common receptor subtypes for
  each neurotransmitter
• Be familiar with examples of the mechanism of
  action of commonly used drugs for each
  neurotransmitter and the diseases they treat

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Advances in Neurochemistry

• Slow neurotransmitters include the monoamines
  and work through G proteins and second
  messengers
• Fast neurotransmitters include GABA and glutamate
  and bind directly on ion-gated channels

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Clinical Neurochemistry

• Monoamines
• Dopamine
• Norepinephrine
• Serotonin
• Others
• Acetylcholine
• GABA
• Glutamate

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Catecholamines

• Dopamine
• Norepinephrine
• Epinephrine

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Dopamine (Main Cell Bodies)

• Long tracts
• Substantia nigra ? primarily to striatum
• Ventral tegmental area ? striatum plus the
  mesolimbic and mesocortical systems
• Intermediate
• Hypothalamicpituitary (DA inhibits prolactin)
• Short
• Olfactory
• Retina

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Weigert stain of the midbrain SNsubstantia
nigra, VTA ventral tegmental area, DR dorsal
raphe
VTA
SN
Dopamine cell bodies and tracts
DR
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Phenylalanine Phenylalanine hydroxylase
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Rate-Limiting Step and Termination of Action of
Dopamine

• Action of tyrosine hydroxylase is the
  rate-limiting step
• The main termination of action for the monoamines
  is presynaptic reuptake
• Monoamine oxidase (MAOB), catechol-O-methyltransfe
  rase (COMT)

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Monoaminergic Receptors

• Formed by 7 membrane spanning regions with an
  intracellular carboxy tail and an intracellular
  amino region
• The structure of the receptors are highly
  conserved with small changes in amino acid
  sequence leading to changes in receptor affinity
• Monoaminergic receptors exert their effect
  through G-proteins and other 2nd, 3rd and 4th
  messengers that often cause protein
  phosphorylation and regulation of an ion channel

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Dopamine Receptors

• D1 is the most common and thought to involve
  stimulation of adenylate cyclase and increased
  production of cyclic AMP
• D1 receptors are found in the striatum but also
  abundantly in cortical and limbic regions
• D2 receptors are located primarily in the
  striatum and inhibit adenylate cyclase
• The D3, D4 and D5 receptors occur primarily in
  cortical and limbic regions

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Drugs that affect the dopaminergic system

• Neuroleptics are classified as typical or typical
  based on their degree of blockade of the D2
  receptor
• Haloperidol is a potent D2 blocker and typical
  antipsychotic. It is an effective antipsychotic
  but can cause Parkinsonism, tardive dyskinesia
  (TD) and cognitive slowing.
• Clozapine is an atypical antipsychotic with weak
  antagonism at D1 and D2 receptors and blocks 5HT2
  serotonin receptors. It may exert its
  antipsychotic effect by blocking D4 receptors,
  thereby sparing the striatum. Clozapine does not
  normally cause extrapyramidal symptoms, TD, or
  increased prolactin.

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Clinical Significance

• Too much dopamine can cause euphoria, confusion
  and psychosis. Too little produces Parkinsonism
• Dopamine does not cross the blood-brain barrier.
  Replace dopamine in Parkinsons disease with
  L-dopa.
• Cocaine blocks reuptake. Amantadine and
  amphetamine promote presynaptic release.
• MAO-B inhibitors such as deprenyl are specific
  for blocking dopamine breakdown at the usual
  doses of 5 mg/bid.

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NE cell bodies are in the locus ceruleus at
the upper dorsal pons.
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Noradrenergic Cell Bodies in the Dorsal Pons
AS
LC
LC
Weigert myelin stain of pons. LClocus ceruleus,
ASaqueduct of Sylvius
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MetabolismTermination

• Reuptakemain route of termination
• COMT ? Normetanephrine MAO ? VMA (3 methoxy 4
  hydroxy-mandelic acid)
• MAO ? MHPG (3 methoxy-4 hydroxy-phenylglycol)

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Alpha and beta receptors in a noradrenergic
synapse
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Noradrenergic Receptors

• Phenoxybenzamine and phentolamine are A1 blockers
  and are used in the treatment of hypertension
• Clonidine is an alpha2 presynaptic autoreceptor
  agonist and causes a decrease in sympathetic
  tone. It is useful in the treatment of
  hypertension and opiate withdrawal
• Yohimbine is primarily an alpha2 presynaptic
  antagonist and causes an increase in sympathetic
  tone which may lead to increased arousal, panic
  anxiety and sexual potency. The beta receptors
  are thought to activate cyclic AMP

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Clinical Significance

• The amygdala is richly innervated by
  nonadrenergic neurons in the locus ceruleus.
  Norepinephrine plays an important role in panic
  disorder, maintenance of attention and
  transmission of pleasurable stimuli via the
  brainstem reticular activating system and medial
  forebrain bundle. NE enhances emotional memories
  and beta blockers can inhibit the formation of
  emotional memories
• There is a dropout of noradrenergic neurons in
  the locus ceruleus in patients with Parkinsons
  disease which may contribute to the high
  incidence of depression and anxiety in PD

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Serotonin

• Cell bodies
• Main cell bodies are in the dorsal raphe nuclei
  surrounding the cerebral aqueduct in the
  midbrain. They project diffusely to the striatum,
  limbic system, cortex and cerebellum. Caudal
  raphe nuclei in the pons and medulla project to
  the spinal cord and probably play a role in the
  mediation of pain in the dorsal horn of the cord

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Synthesis
Availability of tryptophan is the rate limiting
step in serotonin synthesis
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• Metabolism
• Reuptakeprimary method of inactivation
• MAO 5-HIAA
• Clinical significance
• Serotonin has effects on
• Sleep induction
• Mood
• Pain/headache
• Nausea
• Anxiety
• Extrapyramidal system
• Pleasure
• Vasomotor tone
• Psychosis

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Clinical Significance

• Availability of tryptophan is the rate-limiting
  step, Activity of Tryptophan hydroxylase is also
  important
• Reserpine depletes vesicular stores and may
  exacerbate depression
• Fenfluramine promotes presynaptic release
• MAOI pre- and postsynaptically slows metabolism
• Tricyclic antidepressants such as amitriptyline,
  and fluoxetine inhibit reuptake

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Serotonergic Receptors

• A very active area of research. 5-HT1-7 receptors
  have been described subtypes of each group have
  been identified
• 5-HT1 works primarily ? or ? adenylate cyclase,
  Imitrex, used to treat acute migraine, is a 1D
  agonist
• 5-HT receptors affect phosphatidylinositol
  systems methysergide, LSD
• Ondansetron a 5-HT3 antagonist is a potent
  antiemetic

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Serotonin Syndrome

• MSconfusion, agitation, restlessness
• Motormyoclonus, rigidity, hyperreflexia
• Autonomic-shivering, flushing, fever, diaphoresis
• GInausea, diarrhea

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Acetylcholine

• Primary cell bodies
• Found in the patchy forebrain nuclei of the
  nucleus basalis of Mynert and septal nuclei
• Rich connections to the hippocampus and amygdala
• Ach is the main neurotransmitter at the
  neuromuscular jct and in the autonomic nervous
  system
• Termination of action by both
• Enzymatic cholinesterase- choline plus acetate
• By reuptake of choline

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NBMnucleus basalis of Meynert
NBM
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Acetylcholine

• Involved in
• Memory and attention
• Induction of REM sleep
• Regulation of behavior
• Motor function
• Autonomic nervous system

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Clinical Significance

• Choline acetyltransferase (CAT) is the enzyme
  involved in the synthesis of Ach, CAT decreases
  in AD
• Botulinum toxin inhibits release of acetylcholine
  and is useful for the treatment of focal
  dystonia. Lambert-Eaton syndrome, a
  paraneoplastic disorder, leads to decreased
  release of Ach
• Acetylcholinesterase inhibitors such as Aricept,
  Exelon and Reminyl are approved for the Rx of
  mild-mod AD. Reminyl also modulates presynaptic
  nicotinic receptors. Exelon also inhibits
  butyrylcholinesterase
• Mestinon, a peripheral cholinesterase inhibitor,
  improves motor symptoms in myasthenia gravis

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Cholinergic Receptors

• Nicotinic at NMJ and ANS. Antibodies formed
  against nicotinic cholinergic receptors at the
  neuromuscular junction cause myasthenia gravis
• M1-5 muscarinic receptors in the brain. Nicotinic
  receptors also in brain. M2 and 4 decrease cAMP
  and M1,3,5 work via PI
• Atropine and scopolamine block muscarinic
  receptors. Atropine increases heart rate, slows
  GI motility and dilates the pupils. Scopolamine
  can cause memory disturbance. Urecholine, an
  autonomic agonist, promotes bladder emptying.
  Ditropan, an autonomic antagonist, promotes
  retention of urine

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GABA

• Distribution
• The major inhibitory neurotransmitter in the
  brain
• Ubiquitously distributed
• High concentrations in the striatum,
  hypothalamus, spinal cord, colliculi and medial
  temporal lobe
• Synthesis
• Glutamate (amino acid precursor)
• ? Glutamic acid decarboxylase (GAD)
• GABA

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GABA Receptors

• GABA A-chloride channel
• GABA binding opens the chloride channel
• Benzodiazepines enhance GABA affinity and
  activity
• Bicuculline is a receptor antagonist and induces
  seizures
• Barbiturates and alcohol help open the chloride
  channel at another site in the receptor
• Picrotoxin inhibits the chloride channel and
  produces seizures
• GABA is found to be decreased in the striatum in
  Huntingtons disease
• GABA B-Baclofen

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GABA Neuron
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GABA Function

• Benzodiazepines are used to treat anxiety,
  seizures, and muscle spasms
• GABA transaminase inhibitor vigabatrin used in
  Europe for epilepsy
• The anticonvulsant tiagabine (Gabatril) blocks
  reuptake of GABA
• Topiramate (Topamax), divalproex (Depakote),
  gabapentin (Neurontin) and other ACs modulate
  GABA

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Glutamate

• The most common excitatory neurotransmitter in
  the CNS.
• Amino acid involved in excitotoxic injury,
  seizures, learning, memory, anxiety, depression,
  psychosis
• Blockade of glutamate receptors may have a
  protective role for tissue at risk in acute
  stroke and for TBI. MK801 and PCP are NMDA
  antagonists and both cause psychotic symptoms
• Riduzole and lamotrigine medication for ALS and
  epilepsy decrease glutamatergic transmission.
  Memanatine an NMDA antagonist is being tried for
  advanced AD

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Glutamate Receptor Function

• Glutamate, at NMDA receptors, leads to opening of
  an ion channel and influx of Ca and Na
• The block of Mg is removed by activation of an
  AMPA receptor
• Glycine must also bind to its receptor to allow
  Ca and Na influx
• Some glutamate receptors are metabotropic and use
  2nd messengers
• Glutamate reuptake is tightly regulated

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• Feeling stuck?
• Check out the Neurotransmitter Table on p. 73

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Questions
1. Why does cocaine chorea? a. It is a dopamine
agonist b. It reduces GABA levels c. It
enhances serotonin d. It increases endogenous
dopamine 2. Which glutamate reactions are
neurotoxic? a. Glutamate-ACh c.
Glutamate-NMDA b. Glutamate-dopamine d.
Glutamate-serotonin 3. Stimulation of which
dopamine receptor(s) increases adenyl cyclase
activity? a. D1 receptors c. Both D1 and D2
b. D2 receptors d. Neither
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Questions
4. The primary cell bodies for dopamine are
located in the nucleus accumbens? a.
True b. False Matching Type 5.
Dopamine a. Locus ceruleus 6. Serotonin b.
Nucleus basalis of Meynert 7.
Acetylcholine c. Substantia nigra 8.
Norepinepherine d. Dorsal raphe 9.
Dopamine a. Pons 10. Serotonin b.
Midbrain 11. Acetylcholine c. Basal
forebrain 12. Norepinepherine d.
Cerebellum
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Questions
13. What is the rate-limiting step in
norepinepherine synthesis? a. Phenylalanine to
tyrosine d. Tyrosine to dopa b. Tyrosine to
tyrosine e. Dopa to norepinephine
hydroxylase 14. Clozapine does not increase
prolactin. a. True b. False 15. The
activity of the monoamines is primarily
terminated by a. breakdown by MAO d.
phosphorylation b. reuptake into the e.
Ion channel inactivation presynaptic neuron
c. Conversion to choline and acetate
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Answers
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• People and Pills
• and the Art of Medicine

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Surgical Treatment- Cavernous Hemangioma
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9/29/2003
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9/29/2003